This Program Project (PPG) is re-submitted to the NIH with the central objective of studying the molecular mechanisms of susceptibility or tolerance to short term (constant or intermittent) and long term hypoxia in heart, lung and brain. This PPG has three Projects and two scientific Cores, is based at the University of California San Diego (UCSD) and includes scientists from sister institutions (e.g., the Burnham Institute). It is designed to advance biomedical knowledge and make a high impact on our understanding of the basis of cell and tissue tolerance to hypoxia with the purpose to advance our ability to diagnose and treat disease. As a result of all of our preliminary data, we have formulated a PPG with a two-fold thrust: a) To enhance our understanding of the basic and fundamental mechanisms underlying susceptibility or tolerance of specific cells and tissues to constant or intermittently low O2 in the cardio-respiratory system and b) to render susceptible cells in mammals resistant to these stresses, with the ultimate aim to translate basic mechanisms into clinically useful outcomes. Since every Project in this Program has evidence for considering Notch signaling as a central important pathway in hypoxia, each Project centers on Notch and investigates how Notch interacts with other important modulators of Notch activity, whether it is Toll, HIF1, or insulin receptor. The two Cores will be essential to the PPG since they will carry out specific functions that enhance the quality of the science and experiments, cut costs, fosters synergy between Projects and provide an integrative biological view of gene pathways (Systems biology and Animal Hypoxia Cores). The overall Specific Aims of the PPG are: a) To study the adaptive mechanisms to hypoxia in cardiovascular and respiratory systems at both cellular and molecular levels;b) to study the fundamental genetic mechanisms of tolerance in a Drosophila model;c) to modulate/manipulate molecular mechanisms in mammalian cells/tissues/animals to render them hypoxia-tolerant after learning from a tolerant organism, e.g., the fly;and d) to identify molecular signatures of hypoxia tolerance and susceptibility that may be predictive clinically. We believe that this PPG will have a major impact on our understanding of the cellular and molecular mechanisms that underlie a variety of diseases including obstructive Sleep Apnea and its consequential cardiac and neurologic tissue injury, cardiac hypoxia and cardiac muscle injury, Sickle Cell Disease and cardiovascular, respiratory and neurologic injury as well as COPD and cardio-respiratory consequences.